Insulin effects on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart

Stehr, Sebastian; Pexa, Annette; Hannack, S.; Heintz, A.; Heller, Axel R.; Deußen, Andreas; Koch, Thea; Hübler, Matthias

doi:10.1017/s0265021506002109

Cited by 15 publications

(15 citation statements)

References 20 publications

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“…In the case of cardiotoxicity, triglyceride emulsions act themselves as metabolic modulators and at the same time remove the cardiotoxic drug for redistribution. Other metabolic modulators could accomplish similar goals; for example, hyperinsulemic euglycemic therapy provides an inotropic benefit during cardiac pharmacotoxicity [56] and could be coupled with low dose liposomes having similar scavenging benefits to ILE at lower total volumes of lipid [21], a significant concern in lipid emulsion therapy. However, the volume effect contributes significantly to recovery and should not be discounted in the design of future agents…”

Section: Discussionmentioning

confidence: 99%

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion

Fettiplace

Lis

Ripper

et al. 2015

Journal of Controlled Release

105

102

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Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

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Section: Discussionmentioning

confidence: 99%

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion

Fettiplace

Lis

Ripper

et al. 2015

Journal of Controlled Release

105

102

View full text Add to dashboard Cite

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“…Beyond energy production, a number of clinical and experimental observations comport with the conclusion that local anesthetics modify insulin signaling. Hypoglycemic or streptozotocin-induced diabetic animals are more sensitive to bupivacaine cardiac toxicity 40,41 and insulin provides inotropic support during bupivacaine cardiac-toxicity 42,43 . In non-toxic situations, diabetic rats experience extended block durations independent of neurotoxicity 44–47 and patients with poorly-controlled diabetes experience extended duration of local-anesthetic induced peripheral nerve blocks 48–50 ; Despite the importance of understanding the interaction of local-anesthetic effects on diabetic patients 51 , the connection between sensitization to toxicity and glucose handling has previously been incompletely addressed.…”

Section: Discussionmentioning

confidence: 99%

Insulin Signaling in Bupivacaine-induced Cardiac Toxicity

et al. 2016

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Background The impact of local anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5′-adenosine monophosphate–activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE). Methods Sprague–Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3β, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002—a reversible Pi3K inhibitor. Results Bupivacaine cardiotoxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3β to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. Conclusion Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation.

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“…In this study, ROSC was reached faster with higher bupivacaine concentration in insulin-treated animals. The earlier recovery of arterial blood pressure at higher plasma bupivacaine level might be due to the positive inotropic effect of insulin [11]. As expected, ROSR was slower than ROSC because bupivacaine impairs ventricular conduction more than contractility [12].…”

Section: Discussionmentioning

confidence: 99%

“…Glucose was maintained above normal in both groups. The positive inotropic effects of insulin have been shown to be independent of the presence of glucose [11]. Despite of significant decrease in calcium level in both groups, serum calcium was maintained within the normal range throughout the experiment.…”

Section: Discussionmentioning

confidence: 99%

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Insulin Facilitates the Recovery of Myocardial Contractility and Conduction during Cardiac Compression in Rabbits with Bupivacaine-Induced Cardiovascular Collapse

Yang

Uugangerel

Jang

et al. 2012

Anesthesiology Research and Practice

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Bupivacaine inhibits cardiac conduction and contractility. Insulin enhances cardiac repolarization and myocardial contractility. We hypothesizes that insulin therapy would be effective in resuscitating bupivacaine-induced cardiac toxicity in rabbits. Twelve rabbits were tracheally intubated and midline sternotomy was performed under general anesthesia. Cardiovascular collapse (CVC) was induced by an IV bolus injection of bupivacaine 10 mg/kg. The rabbits were treated with either saline (control) or insulin injection, administered as a 2 U/kg bolus. Internal cardiac massage was performed until the return of spontaneous circulation (ROSC) and the time to the return of sinus rhythm (ROSR) was also noted in both groups. Arterial blood pressure, and electrocardiography were continuously monitored for 30 min and plasma bupivacaine concentrations at every 5 min. The ROSC, ROSR and normalization of QRS duration were attained faster in the insulin-treated group than in the control group. At the ROSC, there was a significant difference in bupivacaine concentration between two groups. Insulin facilitates the return of myocardial contractility and conduction from bupivacaine-induced CVC in rabbits. However, recovery of cardiac conduction is dependent mainly on the change of plasma bupivacaine concentrations.

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Insulin effects on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart

Cited by 15 publications

References 20 publications

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion

Insulin Signaling in Bupivacaine-induced Cardiac Toxicity

Insulin Facilitates the Recovery of Myocardial Contractility and Conduction during Cardiac Compression in Rabbits with Bupivacaine-Induced Cardiovascular Collapse

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